1, 4-bis (polyalkyl substituted-4-hydroxy-4-piperidyl) butanes



United States Patent Ofilice 3,086,022 1,4-BIS(POLYALKYL SUBSTITUTED-4-HYDROXY- 4-PIPERIDYL) BUTANES Robert I. Meltzer, Rockaway, and Wilson B. Lutz, Florham Park, N.J., assignors to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware N Drawing. Filed Sept. 25, 1961, Ser. No. 140,214 3 Claims. (Cl. 260--294.7)

The present invention relates to new and novel piperidine derivatives having the formula H30 on, H30 011,

11.0 N R, f on. l t: R:

wherein R is hydrogen or hydroxyl, methyl and R is hydrogen or lower pharmaceutically acceptable HOII tOXiC quaternary ammonium salts thereof.

e compounds of our invention having the above formula have been found to possess significant pharma- R is hydrogen or alkyl, and to the acid' addition and other piperidine We have now found that those compounds of our invention having the formula f R, I 011, R3 3 in which R and R are as described hereinabove may be prepared by the catalytic hydrogenation of compounds of the formula HO CEO-GEO me on, mo on. n30 f R. R. N on. R3 1L3 which are described and claimed in our application Serial No. 140,213, filed September 25, 1961 entitled Piperidine Derivatives, filed concurrently herewith. Palladiconstitute useful catthat those compounds of our invention having lower alkyl substituents on the piperidine prepared from the corresponding compounds having hydrogen substituents on the nitrogen atomsiby conventional alkyla-tion techniques.

Those compounds of our invention having the formula ing hydroxyl substituents at the 4 positions of the piperidine rings by the steps of dehydration to form a diene 3,086,022 Patented Apr. 16, 1963 by catalytic hydrogenation. Dehydration is efboiling in 20 percent sulfuric acid. Hydrogenathose of such acids ylsulfonic, p-toluenesulfonic, sulfonic, sulfuric, phosp oric, cinnamic, hydrochloric, hydrobromic toluenesulfonate and For therapeutic use, our new and novel compounds,

either as the free base or in the form of a salt, may be.

formulated with a conventional pharmaceutical carrier to form tablets, capsules, elixirs, solutions, suspensions, suppositories and the like.

The following examples are included in order further to illustrate our invention: a

EXAMPLE 1 1,4-Bz's (2,2,6,6-Tetramethyl-4-Hydr0xy-4- I Piperidyl)Butane 1,4-bis(2,2,6,6-tetramethyl-4-hydroxy 4 piperidyD- Evaporation of the solvent gives crude material which is recrystallized from -97 petroleum ether to give 1.8 g. (97%) of white needles M.P. 128430.

An additional recrystallization from followed by sublimation of ly pure material, M.P. 128-l29.

petroleum ether gives analytical- Analysz's. Calc.: C, 71.68; H, 12.03; N, 7.60. Found: C, 71.67; H, 12.14; N, 7.62.

EXAMPLE 2 1,4-Bis(1,2,2,6,6-Pentamethyl-4-Hydr0xy-4- Piperidyl)Butane A mixture of 7.37 g. (0.02 mole) of 1,4-bis(2,2,6,6- tetramethyl-4-hydroxy 4 piperidyl)butane, 32 ml. 37%

An analytical sample, M.P. 122 123 is obtained by recrystallizing similar material twice from ligroin and subliming the product.

Analysis.Calc.: C, 72.67; H, 12.20; N, 7.06. Found: C, 72.59; H, 12.22; N, 7.01.

EXAMPLE 3 1,4-Bis(J,2,2,6,6-Pentametkyl-4-Piperidyl) Butane A quantity of 9.2 g. of 1,4-bis(1,2,2,6,6-pentamethyl-4- hydroxy-4-p1per1dyl) butane is refluxed for 6 /2 hours in of potassium sulfate. The filter cake is treated with a little dilute hydrochloric acid and the inorganic material removed by filtration. The filtrate is basified and the product extracted into ether. Evaporat'on of the dried ether solution yields 8.3 g. of a crude product MP. 115-- 116, which reacts rather rapidly with potassium permanganate in acetone indicating incomplete hydrogenation. Recrystallization from methanol raises the M.P. to 116- 117. However, a potassium permanganate test for unsaturation is still positive. An additional recrystallization raises the M1. to 118.6-119.4. Infrared analysis indicates the absence of hydroxyl groups; hence the probable impurity is assumed to be olefinic material rather than undehydrated substances.

The remaining material is then subjected to high pressure hydrogenation in 25% acetic acid at 1800-1900 p.s.i. over a mixture of platinum and palladium on charcoal. Upon basification of the filtered solution the product crystallizes. After recrystallization from methanol it melts at 120-121". Treatment with gaseous hydrogen chloride in ether yields a dihydrochloride salt, MP. 276- 277. One recrystallization from ethanol-ethyl acetate and four recrystallizations from Z-propanol yield 2.5 g. (25%) of the purified dihydrochloride of 1,4-bis(1,2,2, 6,6 pentamethyl 4 piperidyl)butane, M.P. 289-290 (dcc.).

Analysis-Cale: C, 65.87; H, 11.52; Found: C, 65.60; H, 11.46; N, 6.70.

In the foregoing examples, all temperatures are given in degrees centigrade.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of our invention.

Having described our invention what cure by Letters Patent is:

1. A member selected from the group consisting of compounds of the formula we desire to se- HZC q CH: 1130 LCHa 1130 f R; R: f on; R3 R3 4 hydroxy 4 piper- References Cited in the file of this patent UNITED STATES PATENTS 2,624,735 Goldberg et al. Jan. 6, 1953 FOREIGN PATENTS 103,541 Great Britain Feb. 1, 1917 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 1,2-DI(R2-),2,6,6-TRI(CH3-),4-HO,4-((1,2-DI(R3-),2,6,6-TRI(CH3-),4-HO-4 -PIPERIDYL)-CH2-CH2-CH2-CH2-)PIPERIDINE WHEREIN R2 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYXDROGEN AND METHYL AND R3 IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL, AND THE NON-TOXIC PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. 